ISSN: 2320-5407 Int. J. Adv. Res.

11(07), 1234-1240

Journal Homepage: - www.journalijar.com

Article DOI: 10.21474/IJAR01/17342

DOI URL: http://dx.doi.org/10.21474/IJAR01/17342

RESEARCH ARTICLE
ULIPRISTAL ACETATE VERSUS PLACEBO FOR FIBROID TREATMENT

Mbbs, Dgo,Dnb, Jnmch, Amu, Aligarh Assistant Professor Lbkmch (Saharsa).
……………………………………………………………………………………………………....
Manuscript Info Abstract
……………………. ………………………………………………………………
Manuscript History
Received: 31 May 2023
Final Accepted: 30 June 2023
Published: July 2023
Dr. Shipika
Background: The efficacy and safety of oral ulipristal acetate for the
treatment of symptomatic uterine fibroids before surgery are uncertain.
Methods: We randomly assigned women with symptomatic fibroids,
excessive uterine bleeding (a score of >100 on the pictorial blood-loss
assessment chart [PBAC, an objective assessment of blood loss, in
which monthly scores range from 0 to >500, with higher numbers
indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g
per deciliter) to receive treatment for up to 13 weeks with oral ulipristal
acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98
women) or to receive placebo (48 women). All patients received iron
supplementation. The coprimary efficacy end points were control of
uterine bleeding (PBAC score of <75) and reduction of fibroid volume
at week 13, after which patients could undergo surgery.
Results: At 13 weeks, uterine bleeding was controlled in 91% of the
women receiving 5 mg of ulipristal acetate, and 19% of those receiving
placebo (P<0.001 for the comparison of each dose of ulipristal acetate
with placebo). The rates of amenorrhea were 73%, and 6%,
respectively, with amenorrhea occurring within 10 days in the majority
of patients receiving ulipristal acetate. The median changes in total
fibroid volume were −21%,, and +3% (P = 0.002 for the comparison of
5 mg of ulipristal acetate with placebo. Serious adverse events occurred
in one patient during treatment with 5 mg of ulipristal acetate (uterine
hemorrhage) and in one patient during receipt of placebo (fibroid
protruding through the cervix). Headache and breast tenderness were
the most common adverse events associated with ulipristal acetate but
did not occur significantly more frequently than with placebo.
Conclusions: Treatment with ulipristal acetate for 13 weeks effectively
controlled excessive bleeding due to uterine fibroids and reduced the
size of the fibroids.

Copy Right, IJAR, 2023,. All rights reserved.

……………………………………………………………………………………………………....
Introduction:-
Uterine leiomyomas, or fibroids, are benign, hormone-sensitive, smooth-muscle tumors that occur in 20 to 40% of
women of reproductive age.1,2 The most common symptoms are menorrhagia and iron-deficiency anemia, which
may lead to chronic fatigue3 that may not be adequately controlled with iron supplementation alone.4-6 Other
symptoms include pelvic pain, dysmenorrhea, and pressure effects, which may adversely affect quality of life and
fertility.7-10 Many patients require intervention, and the choice of treatment is guided by the patient’s age and

Corresponding Author:- Dr. Shipika 1234

Address:- Mbbs, Dgo,Dnb, Jnmch, Amu, Aligarh Assistant Professor Lbkmch
(Saharsa).
ISSN: 2320-5407 Int. J. Adv. Res. 11(07), 1234-1240

desire to preserve fertility and avoid hysterectomy.10 Fibroids are the most common indication for hysterectomy.1
Other treatments include myomectomy, hysteroscopic removal, uterineartery embolization, and various other
interventions performed under radiologic guidance.10,11 Medical therapies are also available, but these therapies
have limitations. Gonadotropin-releasing hormone (GnRH) agonists can be used as bridging or presurgical
treatments and create an artificial menopausal state, resulting in reversible reduction of uterine and fibroid volume
and aiding in the correction of anemia12-16; however, GnRH agonists frequently cause hot flashes, and the use of
these drugs is approved only for short-term therapy because of safety concerns (loss of bone mineral density).
Progestins are often associated with breakthrough bleeding that limit their use,17 and they may promote
proliferation of fibroids.18-21 The levonorgestrel-releasing intrauterine system can be used in patients who do not
have large uteri distorted by fibroids, but irregular bleeding is frequent, expulsion of the intrauterine device is more
common than in women without fibroids, and the effect on fibroid volume is controversial.22 The role of
progesterone in promoting the growth of fibroids has stimulated interest in modulating the progesterone pathway.
Results from small pilot studies and other uncontrolled trials in which selective progesterone-receptor modulators
such as asoprisnil, mifepristone, telapristone, and ulipristal acetate were used have suggested the potential benefit of
these agents in patients with fibroids.23-26 Ulipristal acetate is a selective progesteronereceptor modulator that acts
on progesterone receptors in myometrial and endometrial tissue and inhibits ovulation without causing large effects
on estradiol levels or antiglucocorticoid activity.27,28 In two small, phase 2 studies (one involving 18 patients and
one involving 38 patients), a 3-month course of ulipristal acetate at a dose of 10 mg per day or 20 mg per day
reduced abnormal bleeding and significantly decreased fibroid volume; there was no advantage of the 20-mg dose
over the 10-mg dose. We conducted the PGL4001 (Ulipristal Acetate) Efficacy Assessment in Reduction of
Symptoms Due to Uterine Leiomyomata (PEARL I) trial to determine the effects of 5 mg of ulipristal acetate per
day and 10 mg of ulipristal acetate per day on uterine bleeding and fibroid volume in women with symptomatic
fibroids who were planning to undergo surgery

Adverse Effects And Complications

The common adverse effects associated with UPA include gastrointestinal symptoms such as nausea and vomiting
and less commonly dry mouth, appetite disorders, diarrhoea, flatulence, altered taste, dry throat and thirst. Other
effects include headaches, back pain, pelvic pain, myalgia, breast tenderness, fatigue, menstrual cycle irregularity,
altered mood and dizziness. The unusual or uncommon side effects include fever, chills, hot flashes, increased risk
of infection, malaise, anxiety, drowsiness, impaired concentration, insomnia, vision disorders, loss of libido, skin
reactions and vulval disorders. Rare complications of the medication include erythema of the eyes, abnormal eye
sensation, syncope, tremor, vertigo, genital itching, painful intercourse and ovarian cyst rupture. It is the reports on
liver injury in the recent time that have led to the temporary suspension of the use of UPA.29

Study design and Oversight

We conducted this randomized, parallel-group, double-blind, placebo-controlled, phase 3 trial from October 2020
through Feb 2020 Department of Obs and Gnae, LBKMCH, Saharsa. The study was approved by the independent
ethics committee at each participating site and was conducted in accordance with the International Conference on
Harmonization Good Clinical Practice guidelines.

Table 1:- Baseline Characteristics of the Modified Intention-to-Treat Population.*

Characteristic Placebo Ulipristal Acetate,

(N = 48) 5 mg (N = 95)

Age-yr 41.6±5.6 41.2±5.9

Body-mass index‡ 24.6±4.4 25.9±4.6
PBAC score§
median 376 386
Total fibroid volume at screening —
cm3
median 61.5 100.7
Hemoglobin — g/dl 9.55±1.18 9.32±1.50
Assessment of pain
Short-Form McGill Pain

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Questionnaire‖
median 8.5 6.5
Visual-analogue scale**
median 16.0 14.0

‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ The pictorial blood-loss assessment chart (PBAC) is a validated method used to objectively estimate blood loss.

Monthly scores range from 0 (amenorrhea) to more than 500, with higher numbers indicating more bleeding.
‖ Scores on the Short-Form McGill Pain Questionnaire range from 0 to 45, with higher scores indicating more severe
pain.
** Scores on the visual-analogue scale range from 0 to 100, with higher scores indicating more severe pain.

study population Women 18 to 50 years of age were eligible if they met the following criteria: a score on the
pictorial blood-loss assessment chart (PBAC, in which monthly scores range from 0 to >500, with higher numbers
indicating more bleeding) higher than 100 during days 1 to 8 of menstruation; fibroid related anemia, defined as a
hemoglobin level of 10.2 g per deciliter or lower without macrocytosis ; a myomatous uterus with a size equivalent
to that of a uterus at 16 weeks or less of gestation; at least one fibroid that was 3 cm or more in diameter, but with no
fibroid measuring more than 10 cm in diameter, as measured by ultrasonography; and a body-mass index (the
weight in kilograms divided by the square of the height in meters) of 18 to 40.

We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the
pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range
from 0 to >500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per
deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (95 women)
or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points
were control of uterine bleeding (PBAC score of <75) and reduction of fibroid volume at week 13

The investigator assigned patients to a study group with the use of a Web-integrated interactive voice-response
system. Study materials and medication packaging were identical for all three groups. Treatment was initiated
during the first 4 days of menstruation. All patients received 80 mg of iron supplementation once daily during the
active-treatment phase. In addition, iron could be prescribed during the screening and follow-up periods at the
discretion of the investigator

Assessment of Uterine Bleeding

Menstrual bleeding was assessed with the use of the PBAC,30 a validated method used to objectively estimate blood
loss. Monthly scores range from 0 (amenorrhea) to more than 500, with higher
numbers indicating more bleeding. Patients were provided with standardized sanitary materials and
recorded the numbers of tampons or pads they used and the extent of soiling with blood (see the

Supplementary Appendix for a sample PBAC and an example of the calculation of the score). Menorrhagia was
defined as a PBAC score of more than 100 during one menstrual period, which corresponds to a blood loss of more
than 80 ml. A PBAC score of 400 corresponds to a blood loss of approximately 300 ml or the use of approximately
80 tampons or pads.30 At screening, patients were taught to use the PBAC and were asked to complete it daily
throughout the treatment period up to week 13 and for 28 days preceding the post-treatment follow-up visits at
weeks 26 and 38. The PBAC score for a 4-week period was calculated from the sum of daily PBAC results for 28
days.

End Points
The coprimary efficacy end points were the percentage of patients with a reduction in uterine
bleeding at week 13, defined as a PBAC score (summed over the preceding 28-day period) of less
than 75, and the change in total fibroid volume from screening to week 13, as assessed by magnetic
resonance imaging (MRI) and read centrally by a radiologist who was unaware of the studygroup
assignments. The total fibroid volume was the sum of the individual fibroid volumes.

Secondary end points included the bleeding pattern (consecutive 28-day PBAC scores); amenorrhea

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(PBAC 28-day score of ≤2 at weeks 9 and 13); reduction in uterine and fibroid volume (i.e., the
percentages of women with at least a 25% reduction); changes in hemoglobin, hematocrit, and
ferritin levels; pain, as measured with the use of the Short-Form McGill Pain Questionnaire31 (which
includes a questionnaire on which scores rangefrom 0 to 45, with higher scores indicating more
severe pain, as well as a visual-analogue scale ranging from 0 to 100, with higher scores indicating
more severe pain); The efficacy analyses were based on the 13-week measurements;

Statistical Analysis
Efficacy analyses were performed according to the intention-to-treat principle. We excluded one patient
in the 5-mg ulipristal acetate group who was withdrawn before she received any study drug.
the statistical tests were two-sided, with a 5% level of significance. Since the planned analyses involved
comparisons 5mg of ulipristal acetate with placebo, a Bonferroni correction was used (all P values
were doubled). No further adjustments for multiplicity have been made, since the efficacy outcome for each dose
group was considered to be successful only if there were significant improvements over
placebo in both coprimary efficacy end points. In general, missing values were imputed for the statistical
analyses with the use of the last available post-baseline value up to the time point of interest.

The percentages of patients with a PBAC of less than 75 at week 13 were compared with the use of a Cochran–
Mantel–Haenszel test (with adjustment for randomization strata), with confidence intervals
calculated with the use of the Newcombe–Wilson score method (uncorrected).32 Additional binary end points were
analyzed in a similar way. For the coprimary end point of the change in total fibroid volume, the data did not meet
the assumptions of parametric tests and were analyzed with the use of the van Elteren extension to the
Wilcoxonbrank-sum test with adjustment for randomization strata, with the Hodges–Lehmann estimator (and
corresponding Moses confidence interval) used for the differences in medians.33The changes from baseline in
PBAC scores and in pain assessments were analyzed in a similar way. Data on uterine volume were log-transformed
and were evaluated with the use of an analysis of covariance; hemoglobin and hematocrit values were analyzed with
the use of a repeated-measures analysis of covariance, with adjustment for the value at screening and for
randomization strata in all analyses. The estimations of the sample size were based on the end point of change in
fibroid volume, since more subjects were needed to show a significant treatment-related difference between the
activetreatment groups and the placebo group for this end point than for the bleeding end point. Assuming a 10%
dropout rate, we estimated that
143 patients would have to undergo randomization (95 in each ulipristal acetate group and 48 in the
placebo group) for the study to have 90% power to show a significant between-group difference, assuming an
average difference of −0.1 (approximately 20% change from baseline) in the change in log10 total fibroid volume
between the ulipristal acetate groups and the placebo group and a
between-patient standard deviation of 0.15.

Results:-
Primary Efficacy End Points
Menstrual bleeding was controlled in 91% of the women who received 5 mg of ulipristal acetate, as compared with
only 19% of the women who received placebo (P<0.001 for the comparison of each ulipristal acetate group with the
placebo group) (Table 2). There were statistically and clinically significant reductions in fibroid volumes in both
ulipristal acetate groups as compared with the placebo group (Table 2

Secondary End Points

There were large reductions in bleeding (median changes in PBAC score of >300) in the patients who
received either dose of ulipristal acetate, whereas there was little change in the patients who received
placebo (P<0.001 for the comparison of each ulipristal acetate group with the placebo group at
weeks 13). The majority of patients in the ulipristal acetate groups, but few patients in
the placebo group, had amenorrhea after 4 weeks of receipt of the study drug (P<0.001 for the comparison of each
ulipristal acetate group with the placebo group). The percentage of patients with a hemoglobin level higher than 12 g
per deciliter and a hematocrit level higher than 36% increased over time in all groups. Hemoglobin and hematocrit
levels were significantly higher in both ulipristal acetate groups than in the placebo group at all time points after the
initiation of treatment A significantly greater percentage of patients in both ulipristal acetate groups than in the
placebo group had a reduction in fibroid volume of at least 25% (P = 0.01) As compared with placebo. 5 mg of

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ulipristal acetate led to reductions in pain (especially moderate or severe pain), as measured with the use of the
Short-Form McGill Pain Questionnaire

The rate of the occurrence of any adverse events did not differ significantly among the three groups.
Headache and pain, discomfort, or tenderness in the breasts were the most common adverse events
in the ulipristal acetate groups, but the events didnot occur significantly more frequently in these
groups than in the placebo group . The rate of hot flashes was low (<3%) in all groups.
Two serious adverse events occurred during thetreatment period: one event of a fibroid protruding
through the cervix (in the placebo group) and one event of uterine hemorrhage (in the 5-mg ulipristal
acetate group).

Table 2:- Key Efficacy End Points in the Modified Intention-to-Treat Population.*
End Point Placebo Ulipristal Acetate, Difference, P Value
(N = 48) 5 mg (N = 95 5 mg Ulipristal
Acetate − Placebo
(95% CI)†
Primary end points
at wk 13
PBAC <75 — 9/48 (19) 86/94 (91) 73 (55 to 83) <0.001
no./total no. (%)
% Change from 3.0 −21.2 −22.6 (−36.1 to 0.002
screening in total −8.2)
fibroid volume‡
median
Secondary end
points
Amenorrhea, PBAC 3/48 (6) 69/94 (73) 67 (50 to 77) <0.001
≤2, at wk 9–12 —
no./total no. (%)
Hemoglobin — g/dl
Baseline 9.55±1.18 9.32±1.50
Week 13 12.61±1.30 13.50±1.32
Change from 3.10±1.68 4.25±1.90 0.92 (0.39 to 1.44) <0.001
baseline to wk 13
Pain assessment
with Short-Form
McGill Pain
Questionnaire
Change from
baseline to wk 13
median -2.5 -5.0 −2.0 (−4.0 to 0.0) 0.10

Discussion:-
In this randomized, double-blind, placebo-controlled trial, oral ulipristal acetate at a dose of 5 mg
per day was effective in controlling excessive bleeding and shrinking fibroids in patients who had severe bleeding
and associated anemia at baseline. Treatment with ulipristal acetate, as compared with placebo, also resulted in
clinically significant increases in hemoglobin and hematocrit levels and reductions in self-reported pain and
discomfort due to fibroids. Current medical therapies for fibroids have
limitations.4,34 Although treatment with a GnRH agonist before surgery results in a lower frequency
of midline incisions, a greater likelihood of vaginal, as compared with abdominal, hysterectomy,
and a reduction in intraoperative blood loss, GnRH agonists cause side effects such as hot flashes and
atrophic vaginitis that may reduce adherence to therapy.12 Pilot and phase 2 trials have previously suggested a
benefit of selective progesterone-receptor modulators for the treatment of fibroids.23-26 This phase 3 trial involving
women with fibroid-related anemia confirms and extends the findings of prior,

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smaller studies.24,25 Heavy menstrual bleeding is a major cause of doctor visits and lost work days.6 In this study,
bleeding was controlled within 8 days after the beginning of the treatment period in the majority of patients in the
ulipristal acetate groups but in few patients in the placebo group. Anemia was corrected from week 5 on in
significantly more patients in the ulipristal acetate groups than in the placebo group. With iron supplementation,
anemia was eventually corrected in most patients in the
placebo group, despite ongoing bleeding. However, iron supplements may have adverse events, and
absorption is variable.35 In our study, the frequency of hot flashes was similar in the ulipristal acetate and placebo
groups. Previous studies involving women treated with ulipristal acetate for up to 6 months identified cases of
progesterone-receptor modulator–associated endometrial changes, including cystic glandular alterations,24,27 but
reversibility was not investigated. A limitation of this study is that the duration of treatment was restricted to 13
weeks. More data are needed to inform the benefits and risks of long-term treatment with ulipristal acetate In
conclusion, treatment with ulipristal acetate (at a dose of 5 mg) for 13 weeks was effective in controlling bleeding,
decreasing fibroid volume, and reducing discomfort in women with menorrhagia and anemia.

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